Martin et al.

BMC Anesthesiology (2018) 18:200

https://doi.org/10.1186/s12871-018-0669-3

REVIEW Open Access

Choice of fluids in critically ill patients

Claude Martin1, Andrea Cortegiani2* , Cesare Gregoretti2, Ignacio Martin-Loeches3,4, Carole Ichai5, Marc Leone6,
Gernot Marx7 and Sharon Einav8,9

Abstract
Background: Fluids are by far the most commonly administered intravenous treatment in patient care. During
critical illness, fluids are widely administered to maintain or increase cardiac output, thereby relieving overt tissue
hypoperfusion and hypoxia.
Main text: Until recently, because of their excellent safety profile, fluids were not considered “medications”.
However, it is now understood that intravenous fluid should be viewed as drugs. They affect the cardiovascular,
renal, gastrointestinal and immune systems. Fluid administration should therefore always be accompanied by
careful consideration of the risk/benefit ratio, not only of the additional volume being administered but also of the
effect of its composition on the physiology of the patient. Apart from the need to constantly assess fluid
responsiveness, it is also important to periodically reconsider the type of fluid being administered and the evidence
regarding the relationship between specific disease states and different fluid solutions.
Conclusions: The current review presents the state of the art regarding fluid solutions and presents the existing
evidence on routine fluid management of critically ill patients in specific clinical settings (sepsis, Adult Respiratory
Distress Syndrome, major abdominal surgery, acute kidney injury and trauma).
Keywords: Fluids, Resuscitation, Critically ill, Crystalloid, Colloid, Intensive care unit

Background overt tissue hypoperfusion and hypoxia. Fluids may expand

Fluids are probably the most commonly administered
intravenous treatment in inpatient care. Because of their
excellent safety profile, until recently fluid solutions were
not considered “medications” [1]. Little to no thought was
therefore invested in the choice of fluids to be adminis-
tered in specific clinical scenarios. However, recent evi-
dence on long-term effects has altered our view on the
different types of fluids available for fluid resuscitation.
Intravenous fluids should be seen as drugs affecting the
cardiovascular, renal, gastrointestinal and immune systems
and should therefore not be administered “blindly”.
Emphasis on the importance of volume above all the
other characteristics of the fluids administered was nur-
tured by early guidelines that focused on administering spe-
cific fluid volumes to hemodynamically unstable patients
(i.e. the surviving sepsis campaign) [2, 3]. It is true that fluid
administration is an important component of treatment of
* Correspondence: andrea.cortegiani@unipa.it
2
Department of Surgical, Oncological and Oral Science (Di.Chir.On.S.). Section
of Anesthesia, Analgesia, Intensive Care and Emergency. Policlinico Paolo
Giaccone. University of Palermo, Via del vespro 129, 90127 Palermo, Italy
Full list of author information is available at the end of the article
the intra-vascular compartment, thereby improving cardiac
output (CO) and end-organ perfusion [3, 4]. However, the
most common error with regards to fluid administration is
the belief that resuscitation hinges on transfusion of a spe-
cific volume of fluids [3, 5].
Disease processes are dynamic and their response to
fluid may change over time. Specific disease states may
also require different fluid therapy. Evidence from peri-
operative settings has associated both hypo- and hypervo-
lemia with several unfavorable outcomes, including acute
kidney injury (AKI), respiratory complications, increased
lengths of stays, admission costs and 30-day-mortality
rates [6, 7]. Later iterations of the guidelines have there-
fore clarified that the aim of fluid resuscitation is restor-
ation of end-organ perfusion and correction of
physiological imbalance. Follow-up during fluid adminis-
tration should therefore include surrogate markers of
organ perfusion (e.g. mean arterial pressure, central ven-
ous oxygen saturation, lactate, CO), markers of circula-
tion, blood electrolyte and acid-base composition and
indicators of renal function [3, 8]. No fluid is ideal for all
disease conditions at all times. This review presents the

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Martin et al. BMC Anesthesiology (2018) 18:200
current state of knowledge regarding the types of
fluids to be administered with an emphasis on several
disease states.
Methods
The concept of this review was put forward during
Euroanesthesia 2015, in the Intensive Care Subcom-
mittee meeting which is open to all attendees. The
subcommittee meeting is typically attended by inten-
sive care physicians who are also anaesthesiologists
with an interest in promoting research in their field.
Following group discussion of several options pro-
posed, the attending subcommittee members selected
this topic as worthy of address. The authors to be
approached were determined based on their previous
contribution to the international literature on specific
related topics and their writing experience. All those
approached agreed to contribute.
For the first section of this paper (“Types of fluid”) a
non-systematic search of Pubmed was performed. For
the second part (“Fluid administration in specific dis-
ease conditions”) the services of a professional librarian
were employed and a systematic search of the literature
was performed. The systematic search was conducted
in both Pubmed™ and Embase™ databases and included
all publications until June 30th 2018. The Cochrane
database is embedded in full in both of these databases
therefore a separate search was not conducted for the
Cochrane database. The key words used were “fluid ad-
ministration” OR “fluid therapy” OR “fluid resuscita-
tion” AND “ICU” OR “critically ill” OR trauma OR
sepsis OR “major abdominal surgery” OR “respiratory
distress syndrome” OR “acute kidney injury”. The filters
applied included human subjects, adults and publica-
tion in the English language. Only studies with original
data (observational, retrospective or prospective), re-
views, systematic reviews and meta-analyses were in-
cluded. After exclusion of duplicate publications this
Fig. 1 Flow diagram of the systematic search of the literature
Page 2 of 14
search yielded 3364 potential papers of interest (see
Additional file 1).
The titles of this list of articles were screened five
times by the authors. Each searched for papers with con-
tent relevant to their specific clinical condition of inter-
est. Screening for sepsis was conducted by CDM and
IML, for major abdominal surgery by SE, for acute re-
spiratory distress syndrome (ARDS) by CG and AC, for
trauma by ML, and for acute kidney injury by CI. Based
on this initial screening 669 papers were selected for re-
view of the abstract. For each section two of the authors
then reviewed the abstracts and selected the articles for
full download. Overall 147 articles were reviewed in full
text (See Fig. 1 for the full publication inclusion/exclu-
sion process). The references of these articles were then
manually screened for additional potentially relevant pa-
pers. The two main selection criteria to determine final
inclusion were relevance to the topic at hand and the
quality of the paper based on expert opinion. For spe-
cific issues, additional seminal studies were used at the
discretion of the authors.
Types of fluids
The following section discusses the characteristics of
most existing fluid solutions. The chemical composition
of many of the solutions currently on the market is pre-
sented in Table 1.
Crystalloids
Given the current controversy surrounding administra-
tion of colloids, crystalloids have prudently been selected
as the first choice for fluid resuscitation. Unbalanced
crystalloid solutions (i.e. saline solutions) typically con-
tain high concentrations of sodium-chloride and have a
pH that is lower than 6.0. In this sense, the term “nor-
mal” saline is a misnomer. The characteristics of saline
solutions depend on their salt concentration (0.9, 0.45,
3% etc.). Balanced crystalloid solutions (e.g. Ringer’s
Martin et al. BMC Anesthesiology (2018) 18:200 Page 3 of 14

Table 1 The chemical composition of commonly used intravenous fluid solutions

Solutions Na+ (meq/L) K+ (meq/L) Cl− (meq/L) Other anions (meq/L) Osmolarity In vivo SIDa
(mosm/L) (meq/L)
Crystalloids
Unbalanced
NaCl 0.9% 154 0 154 – 308 –
NaCl 3% 510 0 510 – 1026 –
NaCl 7.5% 1275 0 1275 – 2395 –
Balanced
Lactate Ringer 130 4 108 Lactate (27.6) 277 27
Acetate Ringer 132 4 110 Acetate (29) 277 27
Acetate Gluconate (Plasmalyte®) 140 5 98 Acetate (27) 294 50
Gluconate (23)
Acetate Malate (Isofundin®) 145 4 127 Acetate (24) 304 27
Malate (5)
Colloids
Unbalanced
Hydroxyethylstarch (Voluven®) 154 0 154 – 308 –
Albumin 154 0 154 – 308 –
Balanced
Hydroxyethylstarch (Tetraspan®) 140 4 118 Acetate (24) 297 29
Malate (5)
Hydroxyethylstarch (Hextend®) 143 3 124 – 307 28
Gelatins 4% (Plasmion®) 154 0 120 – 307 32
Gelatins 3% (Gelofusin®) 150 0 100 – 284 56
a
Strong Ion Difference

lactate, Plasma-Lyte, Isofundine) are buffered by anions
other than chloride. The chloride concentrations of bal-
anced solutions therefore more closely approximate
plasma but their osmolality is lower and they contain al-
ternative anions in non-physiological concentrations.
Lactate-buffered fluids are the least costly in this fluid
category.
Crystalloids, chloride concentrations and renal
failure The concentration of chloride in 0.9% saline so-
lution exceeds that of plasma (154 mEq/L). Experimental
studies have shown that high renal tubular chloride con-
centrations induce renal afferent vasoconstriction with a re-
sultant decrease in renal blood flow and GFR [9, 10]. No
similar effect has been observed with relation to elevated
sodium concentrations [11]. Moreover, canine models dem-
onstrate that when accompanied by hypovolemia, the re-
duction in renal blood flow doubles compared to
euvolemia [11]. In humans, administration of isotonic saline
has been shown to cause hyperchloremic acidosis in both
non critically ill [12] and critically ill patients [13, 14]. In
healthy human volunteers, administration of intravenous
0.9% saline has also been shown to decrease renal blood
flow velocity and renal cortical tissue perfusion when com-
pared to a balanced solution (e.g. plasma-lyte 148) [15].
Summary statements:
 Animal and human studies demonstrate that high
renal tubular chloride concentrations induce renal
afferent vasoconstriction with a resultant decrease in
renal blood flow.
 Given that the availability and cost of saline and
balanced crystalloids are not significantly different,
saline should probably no longer be used for
intravascular volume expansion.
Colloids
Colloids contain macromolecules such as hydroxyethyl-
starch (HES), gelatin, dextran, or albumin. In the past
colloids were thought to be distributed primarily in the
intravascular space and were therefore considered 3–4
times more effective than crystalloids for restoring intra-
vascular volume. Clinical evidence supports the assump-
tion of higher intravascular retention of colloids, albeit
not to such extent. Administration of 1400–1800 ml of
Martin et al. BMC Anesthesiology (2018) 18:200
gelatin, albumin, and HES increases cardiac index by
25–44% in surgical patients while administration of the
same amount of saline (1800 ml) does not affect cardiac
index [16]. Clinical hemodynamic stabilization also
seems to occur more rapidly and with smaller volumes
of colloids compared to crystalloids [17]. Unfortunately,
many studies yielding such evidence were not designed
for this purpose, which limits the validity of their
findings.
Today it is clear that the ratio of intravascular to
administered volume of colloids is usually only 1:1.2
[4, 16–19], far less than previously believed. Large
multicentre, randomised trials have shown ratios < 1:2
[16–19]. Furthermore, many trials noting decreased
transfusion requirements with the use of colloids are
being criticised for bias, as fluid therapy was often
determined by the treating clinicians [17–19].
Hetastarch (HES)
Three large RCTs have associated administration of HES
with AKI and the need for RRT in ICU patients, espe-
cially in those with sepsis [19]. Three randomized con-
trolled studies comparing intraoperative administration
of HES versus crystalloids yielded conflicting results;
HES was responsible for an increased incidence of renal
dysfunction in two studies [20, 21] but no such effect
was observed in the third [22].
The findings from meta-analyses suggest this find-
ing may depend on the patient cohort. Three
meta-analyses (two including general critically ill pa-
tients and one septic patients receiving fluids for re-
suscitation) confirmed the higher risk of AKI but
reported conflicting results for mortality [23–25]. One
further meta-analysis comparing HES to crystalloids
in RCTs of patients without sepsis did not demon-
strate any difference in the incidence of RRT or over-
all mortality. In this analysis, however, the total
volume of fluids administered to patients receiving
colloids was lower [26] raising questions regarding
the parallel protective effect of administration of less
fluids. Two meta-analyses performed in surgical pa-
tients showed that intraoperative HES administration
did not increase either the incidence of AKI or mor-
tality [27, 28].
Nonetheless in 2013, The European Medicines Agency
decided that HES should not be used in critically ill pa-
tients in the EU and the US due to lack of supportive
evidence and some safety concerns [29, 30]. More re-
cently, the Co-ordination group for Mutual recognition
and Decentralised procedures – human (CMDh) of the
European Medicines Agency (EMA) recommended sus-
pension of marketing authorisations for HES (apart from
controlled clinical trials), “because of the risk of kidney
injury and death in certain patient populations” [29].
Page 4 of 14
Albumin
Albumin is the only natural colloid used for intravascular
volume replacement in humans. In the past, administration
of albumin was thought to increase mortality. However, in
2013, a repeat Cochrane meta-analysis found no evidence
of such adverse effect [31]. The multicentre Saline versus
Albumin Fluid Evaluation (SAFE) study performed in 2004
was probably the decisive factor in this reappraisal. In
the SAFE study, no difference was found between
hypovolaemic patients treated with albumin (n = 3497)
or saline (n = 3500) in mortality, length of ICU or
hospital stay, or organ dysfunction [18]. The main
criticisms of the SAFE study are that the presence of
hypovolemia was not determined based on predeter-
mined criteria and that the dose of fluid to be admin-
istered was not preset [18].
Three meta-analyses have studied whether human al-
bumin affects mortality when administered for intravas-
cular volume expansion to critically ill patients with
sepsis [32–34]. These are discussed in greater detail in
the section on sepsis (see below). Taken together, it is
safe to state there is no good-quality evidence regarding
the value of resuscitation of critically ill patients using
albumin.
Summary statements:
 It remains unclear whether albumin confers either
benefit or risk in terms of mortality and renal
function.
 Given the cost of human albumin, it should
generally not be considered the first choice for fluid
replacement unless there is a specific indication for
its use.
Gelatin
Gelatin is a synthetic colloid with a molecular weight of
~ 35 kDa and a relatively short plasma half-life (approxi-
mating 2-3 h). The recent debate on colloids has focused
on the adverse effects of gelatin; namely increased renal
injury, coagulopathy, anaphylaxis and mortality. Unfor-
tunately few studies on gelatin have been sufficiently
powered to reveal valid patient-centered outcomes [31,
35, 36]. Adequately powered controlled, randomised,
double-blinded trials, such as GENIUS-trial which is
currently recruiting (NCT02715466) are required.
Meta-analyses studying potential unwanted effects
of gelatin (predominantly compared to crystalloids)
have not shown increased renal injury, clinically rele-
vant bleeding [36, 37] or even mortality [31, 35, 36,
38]. Bayer et al. used a sequential design to study
three regimens of fluid administration to ICU patients
[39]; HES plus crystalloids, Gelatin plus crystalloids,
and crystalloids alone. The rate of renal replacement
therapy was lower with crystalloids alone. Mortality,
blood transfusion, and allergies did not differ [39, 40].
Martin et al. BMC Anesthesiology (2018) 18:200
Despite the limitations of this study (i.e. confounding
by inconsistent reporting and time-related treatment
changes and differences in the volume of priming)
these have been supported by Moeller et al. who re-
port that German pharmacovigilance data do not in-
dicate gelatin-induced renal injury [36]. Corroboration
can also be found in a recent systematic review which
reported a decreased risk of renal failure with gelatin
when compared to any other intravenous fluid [41].
With regards to allergic reactions, one meta-analysis
reported a significantly greater incidence of allergic re-
sponses with gelatin compared to crystalloids or albumin
[36]. This result was dominated by a single study where
urea-linked gelatine was used [42]. Urea-linked gelatine
is far more allergenic than modified fluid gelatine
(MFG), which exists in most such solutions to-date [43].
Allergic reactions to gelatin are typically mild and their
incidence is much lower when MFG is used compared
to older gelatin preparations [42, 43]. Existing evidence
does not clearly demonstrate that gelatine has more ad-
verse effects. However, the evidence on this topic re-
mains clearly insufficient.
Summary statements:
 The evidence on gelatins remains clearly insufficient;
few RCTs have been sufficiently powered to reveal
valid patient-centered outcomes.
 Observational studies in large cohorts and meta-
analyses comparing gelatine to crystalloids have
mostly shown no different or even lower rates of
renal injury, clinically relevant bleeding and death
with gelatins.
 Allergic reactions are more common and more
severe with urea-linked gelatin than with modified
fluid gelatine but most studies comparing gelatins to
crystalloids/albumin have failed to differentiate be-
tween the two.
Dextrans
The CMDh statement suggests that dextrans may be used
as alternative fluid solutions in routine clinical practice
[29]. This recommendation is somewhat questionable
given the paucity of data regarding dextrans to-date.
Early trials studying EGDT either used no colloids at
all [44] or were not explicit regarding the specific fluid
solutions used [45–47]. The 6S [19], VISEP [17], CHEST
[4], and CRYSTMAS [16] studies included no fluid solu-
tions that contain dextrans. In the CRISTAL trial only
five of the 1414 patients receiving colloids were treated
with solutions containing dextrans [48]. A search of
PubMed using the keywords “dextran/TI AND volume/
AB” (1998 to January 2018) yielded only 17 studies that
describe the use of dextrans in humans and most of
these were small studies focusing on dextran-based
hyperoncotic therapy.
Page 5 of 14
Summary statement:
 The CMDh stated that there are no legal constraints
regarding the use of dextrans for intravascular fluid
replacement at this time. Although this statement is
probably true, there is also an alarming lack of
evidence to support the recommendation to use
these solutions in critically ill humans.
In summary
Balanced crystalloids are generally the solutions of
choice for intravascular fluid resuscitation of hypovol-
aemic patients. The evidence against isotonic saline re-
mains inconclusive but the possible risks associated with
its use are not balanced by any advantage in therapeutic
efficacy or cost at this time. Colloids are probably more
effective than crystalloids, albeit not as effective as theor-
etically expected. However, no additional benefit has
been conclusively proven for colloids over crystalloids.
Therefore, if a decision has been made to administer col-
loids, it should always follow crystalloid administration.
The solutions to consider after failed treatment with
crystalloids should be either albumin or MFG. Regard-
less of the choice of colloids to be used, colloid adminis-
tration should be considered rescue therapy and remain
limited to profound, acute hypovolaemia.
Fluid administration in specific disease conditions
As noted above, there is accumulating evidence that spe-
cific disease states may require different fluid therapy. In
the section below the data supporting this statement is
presented for specific disease conditions often seen in
the ICU (i.e. sepsis, major abdominal surgery, ARDS
trauma and AKI). The guidelines published regarding
fluid administration in these disease conditions are sum-
marised in Table 2. Additional file 2 reports some of the
most relevant articles retrieved by the systematic search.
Sepsis
Lactic acidosis is a major metabolic side effect of sepsis.
As noted above, intravenous administration of 0.9% sa-
line may cause iatrogenic hyperchloremic acidosis [12,
49]. Hyperchloremia has been associated with increase
in mortality in both septic and non-septic patients [50].
However, most studies examining this issue were retro-
spective, which precludes derivation of a meaningful
causative association between the two. Studies compar-
ing solutions with high versus low-chloride concentra-
tions have yielded conflicting results thus far. Reduced
rates of mortality and AKI have been described with bal-
anced solutions [12, 13, 15, 49, 51] therefore until more
information from RCTs is available, balanced solutions
remain preferred over 0.9% saline for the treatment of
hemodynamically unstable septic patients.
Martin et al. BMC Anesthesiology
Table 2 Guidelines on fluid management and resuscitation
Guideline title
Surviving Sepsis Campaign:
international guidelines for
management of sepsis and
septic shock: 2016
The clinical practice
guideline for the
management of ARDS
in Japan
Scandinavian clinical
practice guidelines in
fluid and drug therapy
in adults with acure
respiratory distress
syndrome
European guideline on
management of major
bleeding and coagulopathy
following trauma
AKI in the perioperative
period & in ICU: french
expert recommendations
The table also reports the strenght of recomemantions and GRADE
Albumin
Albumin is the main determinant of plasma oncotic pres-
sure and has a pivotal role in regulating fluid dynamics at
the microvascular level. Albumin also performs other
(2018) 18:200
Authors, year
Rhodes A. et al. 2017 [2]
Hashimoto et al. 2017 [64]
Claesson et al. 2016 [65]
Rossaint et al., 2016 [88]
Ichai C et al.
2016 [111]
Page 6 of 14
Recommendations Grade
We recommend that a fluid challenge technique be Best practice
applied where fluid administration is continued as statement
long as hemodynamic factors continue to improve
We recommend crystalloids as the fluid of choice 1B
for initial resuscitation and subsequent intravascular
volume replacement in patients with sepsis and
septic shock
We suggest using either balanced crystalloids or 2C
saline for fluid resuscitation of patients with sepsis
or septic shock
We suggest using albumin in addition to crystalloids 2C
for initial resuscitation and subsequent intravascular
volume replacement in patients with sepsis and septic
shock when patients require substantial amounts of
crystalloids.
We recommend against using hydroxyethyl starches 1A
(HESs) for intravascular volume replacement in patients
with sepsis or septic shock
We suggest using crystalloids over gelatins when 2C
resuscitating patients with sepsis or septic shock
We suggest fluid restriction in the management of 2B
adult patients with ARDS. Weak recommendation
Moderate quality
evidence
We suggest fluid restriction over a liberal fluid strategy Weak recommendation
in adults with ARDS Moderate quality
evidence
We recommend that fluid therapy using isotonic 1A
crystalloid solutions be initiated in the hypotensive
bleeding trauma patient
We suggest that excessive use of 0.9% NaCl solution 2C
be avoided
We recommend that hypotonic solutions such as 1C
Ringer’s lactate be avoided in patients with severe
head trauma
We suggest the use of colloids be restricted due to 2C
the adverse effects on haemostasis
We recommend not administering hydroxyethylstarch 1B
(HES) in the ICU.
STRONG agreement
We suggest the preferential use of crystralloid instead 2A
of colloid for fluid loading.
STRONG agreement
We suggest preferring balanced solutions in case of 2A
large volume loading.
STRONG agreement
After hemodynamic stabilisation, we suggest avoiding 2A
fluid overload in the ICU.
STRONG agreement
functions that may be relevant for septic patients. These
include stabilization of the glycocalyx, transport of mole-
cules, antioxidant effects, immuno-modulation and posi-
tive inotropic effects.
Martin et al. BMC Anesthesiology (2018) 18:200
In the SAFE trial, patients admitted to the ICU were
randomly assigned to receive albumin or 0.9% saline for
intravascular-fluid resuscitation for 28 days and no dif-
ference was observed in all-cause mortality. However,
the subgroup analysis of septic patients (planned
a-priori) showed an adjusted odds ratio for death of 0.71
(95% CI: 0.52, 0.97, p = 0.03) for albumin [18].
The ALBIOS trial, which compared administration of al-
bumin (target plasma concentration of 30 g/L) to crystal-
loids alone showed no difference in outcomes in the study
population as a whole and in the subgroups of patients
with severe sepsis and septic shock [52]. However, patients
with septic shock who were randomised to receive albu-
min had higher 90-day survival rates (6.3% p = 0.04) [52].
As noted above, three meta-analyses have recently
studied whether human albumin affects mortality when
administered for intravascular volume expansion to crit-
ically ill patients with sepsis [32–34]. Two of these stud-
ies included patients who received crystalloids as well as
synthetic colloids in the control arm. The mortality rates
were equivalent in the two groups in both of these stud-
ies [32, 33]. The third meta-analyses was performed
using only crystalloids as the comparator and did not in-
clude the data from the EARSS trial which was available
only as an abstract [53]. In this meta-analysis, the 90-day
mortality of patients in septic shock was significantly
lower with albumin [34]. This is concordant with an-
other meta-analysis performed in patients with septic
shock [54].
Summary statements:
 Much of data available regarding the type of fluid to
be preferred in patients with sepsis and/or septic
shock comes from subgroup or meta-analyses.
 The data suggests that albumin may reduce
morbidity and survival in patients with septic shock.
 As a rule, volume substitution septic patients should
be undertaken using crystalloids, probably balanced
solutions.
 HES must not be used in critically ill patients, septic
or not.
 If acute hypovolaemia is not responsive to
crystalloids alone, the use of human albumin can be
considered.
Adult respiratory distress syndrome
ARDS was initially considered an inflammatory protein-
rich pulmonary edema accompanied by leakage of
protein-rich fluids into the interstitial space. The result-
ant increase in lung weight was thought to generate atel-
ectasis with eventual impairment of lung mechanics and
gas exchange [55, 56]. However, ARDS has both inflam-
matory edema and hydrostatic components [55, 57, 58].
Development of pulmonary hypertension may lead to an
increase in hydrostatic pressure [55]. Activation of the
Page 7 of 14
renal aldosterone-angiotensin system during mechanical
ventilation also generates high increased intrathoracic
pressure which causes water and salt retention [59, 60].
Fluid loading may improve hemodynamics and oxygen-
ation but it may also worsen lung aeration in patients
with lung inflammation through several mechanisms
[61]. Moreover, a positive fluid balance in patients with
ARDS may increase mortality rate [62].
Data about the best type of fluid in patients with
ARDS are scarce. A recent meta-analysis investigated
the effect of colloids versus crystalloids in patients with
ARDS. Three trials were included for a total of 206 pa-
tients. All the included studies compared albumin versus
saline. The meta-analysis found improved oxygenation
but no survival benefit in patients treated with albumin
versus crystalloid [63]. However, the risk of bias of in-
cluded trials ranged from unclear to high and the sample
size was very low.
Summary statements:
 Fluid management of patients with ARDS has
significantly improved over the last two decades but
many aspects require clarification.
 Conservative strategies seem to lead to better
oxygenation and shorter periods of mechanical
ventilation. Although the evidence supporting it is
still of moderate quality, conservative fluid
administration is recommended in patients with
ARDS [64, 65].
 The type, timing and dose of fluids to be
administered must still be evaluated per-case [53],
taking into account the etiology of ARDS (e.g. burns,
TBI, infection), patient comorbidities and
hemodynamic and respiratory condition [66]
 The type of monitoring used is less important than
the composition of the fluids administered and
overall fluid balance [67–69].
Major abdominal surgery
Fluid administration is part of the perioperative routine
in both elective and urgent major abdominal surgery but
these two situations could not differ more. Elective
major abdominal surgery is often accompanied by bowel
preparation [70–72], preoperative cardiac assessment
when indicated and is performed on a patient that is
hemodynamically stable and adequately hydrated. Con-
versely, patients undergoing urgent abdominal surgery
often suffer severe intravascular fluid depletion due to
both intestinal and extra-intestinal losses (e.g. vomiting,
extra-vascular leakage), are often hemodynamically un-
stable, and have usually undergone little preoperative
assessment.
Elective surgery - The sparse literature addressing peri-
operative fluid administration in patients undergoing
major abdominal surgery refers to elective patients [73].
Martin et al. BMC Anesthesiology (2018) 18:200
Although mechanical bowel preparation is no longer
recommended [74], many patients still undergo
drug-induced bowel preparation. Similarly the evidence-
based recommendation to allow ingestion of clear fluids
up to 2 h before surgery is often translated to fasting
from midnight on the day before surgery [75]. Such
practice may induce dehydration and electrolyte imbal-
ance despite institution of corrective hydration.
In this clinical scenario, intraoperative hydration is
generally titrated to cover the fluid deficit resulting from
bowel preparation and fasting as well as routine fluid
maintenance (2–3 ml/kg/h). With adequate preoperative
preparation however, the fluid deficit in these patients
rarely exceeds 2.5% of body weight. Yet, traditional rehy-
dration during surgery has been shown to result in ad-
ministration of 7 l of fluid on the day of surgery and a
weight gain of 3–6 kg [76–78]. Such practice has led to
the current speculation regarding the impact of peri-
operative fluid administration (both volume and type)
on patient physiology.
One ongoing treatment dilemma is whether adding
vasopressor therapy to fluid administration is beneficial
since such practice may decrease the amount of fluid ad-
ministered. An early meta-analysis of intra-operative
hemodynamic optimization achieved by combining
fluids and vasopressors compared to fluids alone showed
a decrease in both renal and gastrointestinal complica-
tions, but later multicentre trials have yielded mainly
controversial results [79–81]. Most of these studies fol-
low patients either throughout admission or to 28 days
after surgery. However, none present any data regarding
post-operative fluid management, which may have deter-
mined the outcomes sought during this time frame.
Regarding the choice of fluids, most discussion still
surrounds the issue of crystalloids versus colloids [82].
While newer data does not suffice as yet to support the
use of colloids, neither does it suggest that risk is in-
creased. Conversely, there is some evidence that
gastro-intestinal outcomes may even be slightly better
with colloids [83]. This finding is supported by animal
studies suggesting that goal-directed colloid fluid ther-
apy increases microcirculatory blood flow and tissue
oxygen tension in healthy and injured peri-anastomotic
colon compared to goal-directed or restricted crystalloid
fluid therapy [84]. With regards to a direct comparison
between balanced crystalloid solutions versus normal sa-
line, even less literature exists. An RCT comparing these
solutions in major abdominal surgery demonstrated that
balanced solutions caused less electrolyte disturbances,
acid-base disequilibrium and increases in NGAL levels
and were associated with a stronger anti-inflammatory
effect [85].
Urgent surgery - Patients undergoing urgent abdom-
inal surgery often present with sepsis or septic shock.
Page 8 of 14
Therefore, the principles guiding fluid administration in
sepsis should also guide perioperative fluid administra-
tion. An average patient with a hollow viscus perforation
who presents to the department of emergency medicine
is likely to receive at least 1–2 l of crystalloids before
surgery and several litres more during induction of an-
aesthesia and throughout surgery. These should not be
discounted when initiating fluid therapy in the ICU after
surgery. The choice of fluids to be administered should
be determined by timely information regarding acid-base
and electrolyte balance with particular emphasis on
avoidance of an unnecessary chloride load. In the setting
of severe extravascular leakage, intravascular fluid reple-
tion with crystalloids alone may decrease tissue capillary
density, thereby worsening microcirculatory flow dy-
namics and oxygen delivery. An overload of crystalloid
solution may decrease oncotic pressure and viscosity
and exacerbate the inflammatory response [86]. Hence
the importance of considering the type of fluid in further
resuscitation.
Summary statements:
 Adequate preoperative preparation for elective
major abdominal surgery should not induce a fluid
deficit exceeding 2.5% of body weight.
 Most studies regarding fluid administration in the
perioperative setting are limited to early therapy.
 Intraoperative/postoperative rehydration of elective
cases should be performed with a balanced salt
solution. Although this may be accompanied by an
increase in circulating cytokines no clinically
deleterious effect has been observed.
 Colloids may be administered in elective surgery
cases if required- there is no evidence of increased
risk in this patient population and there is evidence
of better gastrointestinal microcirculatory blood flow
and tissue oxygen tension.
 Adding vasopressor therapy to fluid administration
remains controversial - while it likely decreases the
amount of fluid administered it may also decrease
end organ perfusion.
 The principles guiding fluid administration in sepsis
should also guide perioperative fluid administration
in patients undergoing urgent abdominal surgery.
 The crystalloid chosen for patients after urgent
abdominal surgery should be determined
individually, based on patient condition at the time
of ICU arrival.
Trauma
Recent years have seen some interesting changes in fluid
management of trauma patients. Although severe bleed-
ing is the lead cause of death in trauma patients [87],
the European guidelines for management of major
bleeding and coagulopathy following trauma strongly
Martin et al. BMC Anesthesiology (2018) 18:200
recommend restricting volume replacement during
initial trauma resuscitation [88]. This recommendation
is based on data showing not only the feasibility of
this approach but also its advantages in term of both
process (e.g. hospital length of stay) and outcomes
(e.g. survival) [89, 90].
For many years treatment with colloids was considered
particularly efficacious in trauma patients. This concept
was based on the assumption that the vascular endothe-
lium remains intact after trauma (contrary to septic
shock) [91]. Early experimental data supported this as-
sumption, showing that resuscitation with HES 130/0.4
was superior to lactated Ringer [92]. In humans, an ex-
ploratory study of patients monitored with a pulmonary
artery catheter showed similar hemodynamic outcomes
with a lower volume of colloids than crystalloids [93].
However, subgroup analyses of trauma patients included
in the RCTs comparing colloids and crystalloids have
since failed to confirm this assumption with regards to
wither mortality [48] or transfusion requirements [94].
In patients with TBI, mortality was actually higher with
albumin than with saline, probably due to the greater in-
crease in intracranial pressure observed during adminis-
tration of albumin [95]. The European guidelines for
management of major bleeding and coagulopathy follow-
ing trauma therefore recommend isotonic crystalloids ra-
ther than colloids for initial resuscitation of hypotensive
bleeding trauma patients [88].
Among crystalloid solutions, the respective roles of
balanced solutions and saline remain controversial. Un-
surprisingly, administration of lactated Ringer solution
increases plasma lactate concentrations, whereas normal
saline increases the base deficit [96]. In patients with se-
vere TBI, hypotonic solutions (including lactated Ringer)
should be avoided as they exacerbate cerebral edema.
Conversely, balanced solutions cause less hyperchlore-
mic acidosis than saline in these patients [97]. A RCT of
adult trauma patients requiring blood transfusion, intub-
ation, or operation within 60 min of arrival showed that
pre-hospital resuscitation with Plasma-Lyte A yielded
better acid-base status and less hyperchloremia 24-h
after injury compared with saline [98]. To summarise -
the use of balanced solutions seems promising for
trauma resuscitation but currently remains under inves-
tigation [99].
There is ongoing debate regarding intravascular vol-
ume expansion with hypertonic saline in trauma patients
[100, 101]. Han et al. randomized 294 patients with
hypovolemic shock after trauma to receive 3% hyper-
tonic saline (n = 82), 7.5% hypertonic saline (n = 80), or
lactated Ringer (n = 84) [102]. Although baseline popula-
tion characteristics were similar in the three groups, pa-
tients receiving hypertonic solutions (3% or 7.5%) were
given about half the amount of fluids than those given
Page 9 of 14
lactated Ringer within the first hour, a difference which
disappeared within 24 h. Some side effects (e.g.
arrhythmia, hypernatremia) were more commonly ob-
served in patients receiving 7.5% hypertonic saline,
whereas others (e.g. renal failure, coagulopathy, pulmon-
ary edema) were more prevalent among patients receiv-
ing lactated Ringer. The authors concluded that among
the solutions examined 3% hypertonic saline has the best
safety and efficacy profile [102]. With regards to colloids
- the relative contribution of micro-circulatory abnor-
malities, endothelial dysfunction, local and systemic in-
flammatory processes and oxidative stress differs
between hemorrhagic and septic shock. Decreased tissue
perfusion is a major component of haemorrhagic shock
whereas inflammatory processes are likely more pre-
dominant in septic shock. Hence the effects of HES may
also differ. Evidence supporting the presence of a differ-
ence includes three meta-analysis showing that the use
of HES was not associated with renal effects or clinically
significant coagulopathy in the OR [27, 28, 103]. Simi-
larly, no study found deleterious effects of HES in early
resuscitation of trauma patients [104]. The European
Medicine Agency decided that HES can still be used in
surgical patients, and for management of hemorrhagic
shock following an initial fluid challenge with crystal-
loids that has failed. However the clinician should be
aware that colloids have not been associated with an im-
provement in survival in patients with trauma, burns or
following surgery [31].
Summary statements:
 In the hypotensive trauma patient, crystalloids
should be administered initially and the amount of
fluids administered should be restricted.
 Colloids and hypertonic solutions may accelerate
achievement of hemodynamic goals, but have been
associated with clinically important side effects and
have not been shown to decrease mortality.
Therefore these solutions should not be used as first
line therapy.
 Albumin and hypotonic saline should not be
administered to patients with TBI.
 The debate between balanced crystalloids and
normal saline in trauma remains open, but balanced
crystalloids are preferred for large volume
resuscitation.
Acute kidney injury
Fluid administration is one of the cornerstones of pre-
vention of AKI. As with any other body organ, the goal
of fluid therapy in this clinical scenario is restoration of
intravascular volume with secondary improvement in
kidney perfusion pressures and a resultant improvement
in local tissue oxygenation. However, the precise rela-
tionship between hypo/hypervolemia and AKI remains
Martin et al. BMC Anesthesiology (2018) 18:200
unclear. Studies differ substantially in case mix, fluid vol-
umes and types and the timing of fluid administration.
Regardless of the cause and/or mechanism of AKI,
macro-circulation alterations (i.e. changes in renal blood
flow) are associated with micro-circulation abnormalities
(tissue perfusion), endothelial dysfunction, local and sys-
temic inflammatory processes and oxidative stress [105].
The relative contribution of each of these to the devel-
opment of AKI differs dependent on the cause of renal
injury [105]. Whereas decreased tissue perfusion is a
major component of haemorrhagic shock, inflammatory
processes may be more predominant in AKI caused by
septic shock [105]. Patients with sepsis seem particularly
susceptible to the deleterious effects of hypervolemia on
kidney function [106]. The importance of microcircula-
tory changes in this clinical scenario makes the choice of
fluids all the more crucial.
Gelatins and albumin
Few studies have assessed the potential renal toxicity of
gelatins [36, 38, 107]. An RCT comparing gelatins and
crystalloids for fluid resuscitation in septic patients is
currently ongoing (NCT 02715466). The RARE trial
compared albumin to cystalloids in ICU patients and
failed to demonstrate any increase in the risk of AKI
[52].
Summary statements:
 Administration of HES increases the incidence of
AKI and RRT in critically ill patients. The use of
HES is therefore no longer approved for these
patients, regardless of cause of admission.
 No increase has been observed in the rate of AKI in
surgical patients or in patients with haemorrhagic
shock treated with HES.
 Administration of HES as a second line fluid
solution reduces the overall volume of fluid
administered to patients.
 The European Medicines Agency suggests that HES
is optional as a second line fluid therapy following
crystalloids in surgical patients, provided they are
not septic or critically ill. This statement requires
validation with additional RCTs.
 The data regarding gelatins or albumin in patients at
risk of AKI is too sparse to draw meaningful
conclusions.
Balanced versus unbalanced fluids
The clinical benefit of balanced-fluid resuscitation on
renal function remains controversial [14]. A single center
trial that compared chloride-liberal (saline, 4% gelatin, 4%
albumin) to chloride-restrictive (lactated crystalloid, bal-
anced crystalloid, 20% albumin) fluid administration in a
nonselective cohort of 1500 ICU patients reported more
renal dysfunction in the chloride-liberal group [13].
Page 10 of 14
However, these findings must be interpreted with caution;
the difference observed between the groups may have re-
sulted not only from the dose of chloride administered
but also from other potentially beneficial measures imple-
mented only in the study group [13]. The large
double-blind, cluster-randomized, double cross-over trial,
compared 0.9% Saline versus Plasma-Lyte 148 for ICU
fluid therapy (SPLIT) in 2300 hypovolemic patients [51].
No difference was found in the incidence of AKI, RRT be-
tween the 2 groups. However, both study and control
groups received less fluids than expected; only 2655 ±
3052 and 2554 ± 2120 ml of study fluids were adminis-
tered respectively during the 5-day study period. More-
over in the SPLIT trial, the patients were not severely ill
and plasma chloride levels were not measured. A
meta-analysis of critically ill and surgical patients showed
no difference in the rates of mortality and RRT with bal-
anced solutions when compared to unbalanced solutions
[108]. However, meta-analyses on this topic are limited by
large heterogeneities in case mix, fluid volumes and dur-
ation of exposure, underpowering, imprecision, and more.
In 2018, two large-scale randomized studies compar-
ing balanced crystalloids versus saline were published,
one in critically ill, and one in non critically ill patients
[109, 110]. Among the 13,347 non-critically ill patients
treated in the emergency department, there was no dif-
ference in hospital free days [110]. The trial comparing
balanced crystalloids (Ringer’s solution or plasma-Lyte)
to saline in 15,802 critically ill adults showed that the
administration of balanced solutions resulted in lower
rates of the composite outcome sought (death from any
cause, new renal-replacement therapy, or persistent
renal dysfunction) [109].
In practice, the systematic use of balanced solutions
is not recommended in patients who are not critically
ill yet and require low volume resuscitation. Experi-
mental data and large observational studies support
potential deleterious renal effects of unbalanced solu-
tions related to severe hyperchloremia. The above
mentioned large randomized trial in critically ill pa-
tients concluded that the use of balanced solution re-
sulted in less use of renal replacement therapy, less
persistent renal dysfunction, and higher survival [109].
A strategy favouring the use of balanced fluids in se-
vere ICU patients requiring high fluid volume resusci-
tation is recommended [111, 112].
Summary statements:
 If a large volume of fluid is likely to be required for
resuscitation, especially in septic patients, balanced
fluid solutions should be selected as these may
reduce the likelihood of AKI.
 Despite controversial data, balanced solutions for
fluid resuscitation can be favoured even in with
small amount of fluids as they may reduce the
Martin et al. BMC Anesthesiology (2018) 18:200
incidence of persistent renal dysfunction and the use
of RRT.
 NaCl 0.9% remains useful for patients with
hypochloremic alkalosis
Future directions
In many patients stabilization of the systemic hemodynamic
condition is not immediately accompanied by improvement
in microcirculatory parameters. This situation may persist
for hours or days, indicating long-lasting tissue ischemia
[113]. Ongoing microcirculatory derangement is associated
with increased morbidity and mortality, even when global
hemodynamics are compensated [114]. Studies incorporat-
ing data on the effect of various fluids on the microcircula-
tion are needed [115]. Dark-field microscopy, a new
technique for measuring microcirculation, may offer im-
portant information regarding the microcirculatory changes
occurring during administration of various fluids in specific
disease conditions [116].
Conclusions
Intravenous fluids are drugs and should be prescribed as
such. Among the available fluids, crystalloids have the
highest benefit/risk ratio and, should generally be pre-
scribed first. For critically ill patients or when large
amount of fluids is expected to be infused, balanced so-
lutions should be preferred because of their favourable
effects on patient outcomes, including kidney function.
The preferred solution for non critically ill patients or
low volume resuscitation is less clear. However, given
the availability of balanced solutions and their low cost,
they could be considered for all patients. The role of al-
bumin remains a matter of debate, but there is indirect
evidence that albumin may favourably affect the out-
comes of patients with septic shock. The indications and
effects of gelatins remain unclear for critically ill pa-
tients. The role of dextrans in this patient population
should probably remain marginal until more data is
forthcoming.
Additional files
Additional file 1: Output of the systematic search. Description of data:
Excel table reporting the output of the systematic search (XLSX 485 kb)
Additional file 2: Most relevant studies on fluids in critically ill patients
discussed in the main text. Description of data: Table reporting relevant
studies on fluids in critically ill patients retrieved by the systematic search
(DOCX 151 kb)
Abbreviations
AKI: Acute kidney injury; ARDS: Acute respiratory distress syndrome;
CI: Cardiac index; CO: Cardiac output; CVP: Central venous pressure;
EGDT: Early-goal directed therapy; GFR: Glomerular filtration rate;
HES: Hydroxyethyl-starch; ICU: Intensive Care Unit; MFG: Modified fluid
gelatine; NGAL: Neutrophil gelatinase-associated lipocain; PLR: Passive leg
raising; RBF: Renal blood flow; RCT: Randomized controlled trial; SBP: Systolic
Page 11 of 14
blood pressure; SOFA: Sequential Organ Failure Assessment; SV: Stroke
volume; TBI: Traumatic brain injury
Acknowledgments
We thank Dr. Iris Arad for her invaluable help with the literature search.
Funding
None
Availability of data and materials
All data can be retrieved in the manuscript and its supporting information file.
Authors’ contributions
CM, CG, AC, IML, CI, ML, GM, SE contributed equally in conceiving the
content of the review and writing the manuscript. All authors read and
approved the final version of the manuscript.
Ethics approval and consent to participate
Not applicable
Consent for publication
Not applicable
Competing interests
Dr. Leone declares fees for lectures from Octapharma, LFB, Aguettant
Pharma. Dr. Marx received honoraria for lecturing and grants from BBRAUN.
He is also the coordinator of the German guidelines on fluids. He is also an
Associate Editor for BJA and the principal investigator of the Gelatin in ICU
and Sepsis (GENIUS) trial. Dr. Cortegiani is an Associate Editor for BMC
Anesthesiology. Dr. Martin, Dr. Einav, Dr. Martin-Loeches Dr. Icai and Dr. Gre-
goretti declare no conflict of interest.
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in
published maps and institutional affiliations.
Author details
1
Department of Anesthesia, Intensive Care and Trauma Center, Nord
University Hospital, Aix Marseille University, APHM, Marseille, France.
2
Department of Surgical, Oncological and Oral Science (Di.Chir.On.S.). Section
of Anesthesia, Analgesia, Intensive Care and Emergency. Policlinico Paolo
Giaccone. University of Palermo, Via del vespro 129, 90127 Palermo, Italy. 3St
Jame’s hospital and Trinity College Dublin, Dublin, Ireland. 4Universidad de
Barcelona. CIBER, Barcelona, Spain. 5Adult Intensive Care Unit, Université Côte
d’Azur, University Medicine of Nice, Nice, France. 6Department of
Anesthesiology and Critical Care Medicine, Aix Marseille University, Assistance
Publique Hopitaux de Marseille, Marseille, France. 7Department of Intensive
Care Medicine, University Hospital RWTH Aachen, Aachen, Germany. 8Surgical
Intensive Care Unit, Shaare Zedek Medical Centre, Jerusalem, Israel. 9Hebrew
University Faculty of Medicine, Jerusalem, Israel.
Received: 30 August 2018 Accepted: 12 December 2018
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